Malignant tumor cells are invasive by degrading such host barriers as basal lamina and connective tissues. Since collagen constitutes the primary structural component of these barriers, invasiveness must involve the degradation of collagen. We propose that this is achieved by the elaboration of specific collagenolytic activity from the invading cells. Nevertheless, certain connective tissues such as hyaline cartilage resist invasion. This selective resistance to invasion is obviously determined by tissue specific anti-invasive principles which may express themselves as a physical barrier to invasion or a system translated into the specific inhibition to the penetration by tumor cells. Indeed, cartilage contains a low molecular weight protease inhibitor (5) which is able to inhibit collagenolytic activity and which after extraction makes the cartilage penetrable to tumor cells. Similar protease inhibitors have since been found in other connective tissues including bovine urinary bladder. In this proposal, we shall study the concept of collagenolytic activity as a proximal event in the acquisition of an invasive potential by tumor cells and define interrelationships between tumor protease (collagenase) activity, host protease (collagenase) inhibitor(s) and, tumor growth characteristics in cell lines derived from chemical carcinogen (FANFT)-induced transitional cell carcinomas arising in the urinary bladder of the Fischer rat. The FANFT-model is particularly well suited for the goals of this proposal, since FANFT tumors pass through a well-defined and reasonably long preinvasive stage of development before becoming invasive; thus, allowing to study cells derived from preinvasive and invasive bladder tumors.